Prostate cancer is the most common cancer in United States males, with an estimated 186,320 new cases in 2008, accounting for 25% of cancer incidence and 10% of cancer deaths (Cancer Facts and Figures, 2008, American Cancer Society, Atlanta, Ga.). Prostate cancer develops slowly in the majority of cases; however progression to metastasis is highly lethal and can occur rapidly. Significant progress has been made in recent years in the understanding of molecular mechanisms responsible for prostate cancer initiation and progression, but therapeutic approaches for the treatment of prostate cancer remain limited. Treatments to prevent metastasis include radical prostatectomy and radiation therapy, both of which carry significant risk to urinary and sexual function. Metastatic prostate cancer can be treated with androgen ablation therapy, but almost uniformly results in hormone-refractory disease leading to mortality. Although localized prostate tumors are usually curable, diagnosis of prostate cancer remains a difficult, inexact process and treatment can result in side effects that significantly impact quality of life (The Prostate-Specific Antigen (PSA) Test: Questions and Answers, 2007, U.S. National Institutes of Health, Bethesda, Md.; Early Prostate Cancer: Questions and Answers, 2007, U.S. National Institutes of Health, Bethesda, Md.). Metastatic prostate cancer is highly resistant to therapeutic intervention and is almost uniformly lethal. Therefore, the development of effective novel targeted therapies to inhibit prostate cancer progression and metastasis will have a significant impact on prostate cancer mortality.
Multiple genetic and epigenetic changes take place during human prostate cancer initiation and progression (Vasioukhin, 2004 Cell Cycle 3, 1394-1397; Bradford et al., 2006 Urol. Oncol. 24, 538-551). Hepsin (HPN) is one of the most upregulated genes in human prostate cancer and encodes a type-II transmembrane serine protease that is overexpressed in up to 90% of prostate tumors with levels often increased >10 fold (Magee et al., 2001 Cancer Res 61, 5692-5696; Dhanasekaran et al., 2001 Nature 412, 822-826; Stamey et al., 2001 J. Urol. 166, 2171-2177). Hepsin is upregulated early in prostate cancer initiation and is maintained at high levels throughout progression and metastasis. In addition, hepsin is also overexpressed in ovarian and renal carcinomas (Tanimoto et al., 1997 Cancer Res 57, 2884-2887; Zacharski et al., 1998 Thromb Haemost 79, 876-877; Betsunoh et al., 2007 Cancer Sci. 98(4):491-8) and in endometrial cancer (Matsuo et al., 2008 Anticancer Res. 28(1A):159-64).
Significant evidence indicates that hepsin overexpression plays an important role in the promotion of prostate cancer progression and metastasis. Hepsin upregulation in a transgenic mouse model of localized prostate cancer promoted progression, causing the transition of nonmetastatic cancer into an aggressive carcinoma with metastasis to bone, liver and lung (Klezovitch et al., 2004 Cancer Cell 6, 185-195). The cellular context and level of hepsin expression appear to be important to the phenotype, as high levels of hepsin overexpression in a prostate cancer cell line reduced cell proliferation and invasion (Srikantan et al., 2002 Cancer Res 62, 6812-6816). While the molecular mechanisms responsible for hepsin function in prostate cancer in vivo are unknown, in vitro evidence indicates that hepsin can activate pro-urokinase plasminogen activator (pro-uPA) and pro-hepatocyte growth factor (pro-HGF) (Moran et al., 2006 J Biol Chem 281:30439-30446; Kirchhofer et al., 2005 FEBS Lett 579:1945-1950). Activation of the uPA cell-surface serine protease system and HGF-Met scattering pathway may be responsible for promotion of metastasis by hepsin, and is consistent with the observed basement membrane disruption in mouse prostates overexpressing hepsin (Klezovitch et al., 2004 Cancer Cell 6:185-195).
Protease-targeted drugs have proven to be clinically useful for treatment of HIV and hypertension and have shown potential in the treatment of cancer, obesity, cardiovascular, inflammatory and neurodegenerative diseases (Fear et al., 2007 Pharmacol Ther 113:354-368). For example, WX-UK1 is a potent small-molecule inhibitor of uPA developed by Wilex and has shown potent antitumor and antimetastasis activity in a rat breast cancer model (Abbenante et al., 2005 Med Chem 1:71-104). WX-UK1 has completed phase Ib trials in patients with solid tumors and is currently in combination phase I trials with capecitabine in patients with breast cancer and other solid tumors.
Despite such advances as the recognition of hepsin upregulation in prostate cancer, ovarian carcinoma, endometrial cancer, and renal cell carcinoma, neither this example of cancer-related aberrant gene expression nor other potential targets for anti-cancer therapeutic intervention have yielded safe and effective therapies to block cancer progression or prevent metastasis. For example, invasive or micrometastatic prostate cancers are largely unresponsive to standard cytotoxic drugs used in other areas of oncology (e.g., DNA-binding or DNA-disrupting agents), and use of these cytotoxic agents is generally accompanied by a host of undesirable side-effects associated with their effects on normal, healthy tissues. The unusual androgen dependence of prostate tumors has made androgen ablation therapy a temporarily effective clinical strategy for management of prostate cancer, but androgen-independent tumor recurrence within a median of two to three years is common and is typically untreatable (Feldman et al., 2001 Nat. Rev. Cancer 1:34-45).
Clearly there remains a significant unmet need for more and better anti-cancer agents, including agents that are capable of preventing cancer progression and/or blocking metastasis, and preferably further including agents having little or no cytotoxicity toward non-malignant cells, and that can be conveniently administered. Effective agents to prevent disease progression would reduce the need for surgical or radiation-based therapies, and could have a significant impact on prostate cancer related mortality. The present invention addresses these needs and offers other related advantages.